US6989443B2ExpiredUtilityA1
Carboranylporphyrins and uses thereof
Est. expiryJun 28, 2024(expired)· nominal 20-yr term from priority
A61K 49/106A61K 51/0485A61K 41/0095C07D 487/22A61K 41/0071C07F 1/08C07F 5/00C07F 1/00C07F 3/00
77
PatentIndex Score
6
Cited by
47
References
56
Claims
Abstract
The present invention is directed to low toxicity boronated compounds and methods for their use in the treatment, visualization, and diagnosis of tumors. More specifically, the present invention is directed to low toxicity carborane-containing 5, 10, 15, 20-tetraphenylporphyrin compounds and methods for their use particularly in boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) for the treatment of tumors of the brain, head, neck, and surrounding tissue. The invention is also directed to using these carborane-containing tetraphenyl porphyrin compounds to methods of tumor imaging and/or diagnosis such as MRI, SPECT, or PET.
Claims
exact text as granted — not AI-modified1. A compound of the formula
wherein:
Y 1 , Y 2 , Y 3 , and Y 4 are independently on the ortho, meta or para position on the phenyl rings, and are independently hydrogen, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, or an alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, or heteroaryl group substituted with 1 to 4 hydrophilic groups selected from hydroxy, alkoxy, —C(O)OR 5 , —SOR 6 , —SO 2 R 6 , nitro, amido, ureido, carbamato, —SR 7 , —NR 8 R 9 , or poly-alkyleneoxide; or
a substituent represented by the formula
wherein D represents independently, Z, hydrogen, or a substituent represented by the formula
provided that at least one D is Z or is represented by formula (3);
wherein D′ represents independently, Z, hydrogen, or a substituent represented by the formula
provided that when q is 0, or when q is not zero and D′ is solely hydrogen, then at least one D is represented by Z, or when q is not zero and D′ is represented by formula (4) and r is zero, then at least one D is represented by Z;
Y 5 , Y 6 , Y 7 , and Y 8 are independently on the ortho, meta or para position on the phenyl rings, and are represented by the formula
—X a —(CR a R b ) v —Z (5);
W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are hydrophilic groups independently on the ortho, meta or para position on the phenyl rings, and are independently selected from hydroxy, alkoxy, —C(O)OR 5 , —SOR 6 , —SO 2 R 6 , nitro, amido, ureido, carbamato, —SR 7 , —NR 8 R 9 , or polyalkylene oxide;
X a , X 1 , X 2 , X 3 , and X 4 are independently oxygen or sulfur;
R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently selected from hydrogen and C 1 to C 4 alkyl;
Z is a carborane cluster comprising at least two carbon atoms and at least three boron atoms, or at least one carbon atom and at least five boron atoms, within a cage structure;
n, p, s, t, and v independently represent 0, or an integer from 1 to 20;
m independently represents 1, 2, or 3;
q and r independently represent 0, 1, 2, or 3;
a, b, c, and d independently represent 1 or 2;
k, l, u, and w independently represent 0, 1, or 2;
e, f, g, h, i, and j independently represent 0, or an integer from 1 to 5;
provided that at least one of Y 1 , Y 2 , Y 3 , and Y 4 represents formula (2); each of the sums a+e+k, b+f+l, c+g+u, h+d+w, q+i, r+j, independently represents an integer from 1 to 5; when any of k, l, u, or w is not zero, then at least one of Y 1 , Y 2 , Y 3 , and Y 4 represents formula (2); and
M is either two hydrogen ions; a single monovalent metal ion; two monovalent metal ions; a divalent metal ion; a trivalent metal ion; a tetravalent metal ion; a pentavalent metal ion; a hexavalent metal ion; a radioactive metal ion useful in radioisotope-mediated radiation therapy or imageable by single photon emission computed tomography (SPECT) or positron emission tomography (PET); a paramagnetic metal ion detectable by magnetic resonance imaging (MRI); a metal ion suitable for boron neutron capture therapy (BNCT) or photodynamic therapy (PDT); or a combination thereof; wherein the porphyrin-metal complex derived from a single monovalent metal ion is charge-balanced by a counter cation, and the porphyrin-metal complex derived from a trivalent, tetravalent, pentavalent, hexavalent metal ion is charge-balanced by an appropriate number of counter anions, dianions, or trianions.
2. The compound according to claim 1 wherein Z is selected from the carboranes —C 2 HB 9 H 10 or —C 2 HB 10 H 10 , wherein —C 2 HB 9 H 10 is nido ortho-, meta-, or para-carborane, and —C 2 HB 10 H 10 is closo ortho-, meta-, or para-carborane.
3. The compound according to claim 1 , wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.
4. The compound according to claim 1 wherein a, b, c, and d are 1, and Y 1 , Y 2 , Y 3 , and Y 4 are represented by
5. The compound according to claim 4 wherein D is Z, wherein Z is selected from the carboranes —C 2 HB 9 H 10 or —C 2 HB 10 H 10 , wherein —C 2 HB 9 H 10 is nido ortho-, meta-, or para-carborane, and —C 2 HB 10 H 10 is closo ortho-, meta-, or para-carborane.
6. The compound according to claim 5 , wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.
7. The compound according to claim 6 , wherein X 1 and X 2 are O; R 1 , R 2 , R 3 and R 4 are H; n and p are 1; and m is 2.
8. The compound according to claim 7 wherein Y 1 , Y 2 , Y 3 , and Y 4 are in a meta position on each phenyl ring.
9. The compound according to claim 8 wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 5 positions on each phenyl ring.
10. The compound according to claim 8 wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 4 positions on the phenyl ring.
11. The compound according to claim 9 wherein e, f, g, h, k, l, u, and w are 0.
12. The compound according to claim 7 , wherein e, f, g, and h are 1 and k, l, u, and w are 0.
13. The compound according to claim 12 , wherein W 1 , W 2 , W 3 , and W 4 are independently, hydroxy or alkoxy.
14. The compound according to claim 13 , wherein W 1 , W 2 , W 3 , and W 4 are alkoxy.
15. The compound according to claim 14 , wherein alkoxy is methoxy.
16. The compound according to claim 15 , wherein Y 1 , Y 2 , Y 3 , and Y 4 are in the para position on each phenyl ring.
17. The compound according to claim 16 , wherein W 1 , W 2 , W 3 , and W 4 are in a meta position of each phenyl ring.
18. The compound according to claim 17 wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 5 positions of each phenyl ring.
19. The compound according to claim 17 wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 4 positions of the phenyl ring.
20. The compound according to claim 9 wherein k, l, u, and w are 1.
21. The compound according to claim 20 , wherein Y 5 , Y 6 , Y 7 , and Y 8 are in the para position on each phenyl ring.
22. The compound according to claim 21 wherein the —X a —(CR a R b ) v —Z substituents are in the 3 and 5 positions on each phenyl ring.
23. The compound according to claim 21 wherein the —X a —(CR a R b ) v —Z substituents are in the 3 and 4 positions on the phenyl ring.
24. The compound according to claim 22 or 23 wherein X a is O; R a and R b are H; v is 1, and Z is selected from the carboranes —C 2 HB 9 H 10 or —C 2 HB 10 H 10 , wherein —C 2 HB 9 H 10 is nido ortho-, meta-, or para-carborane, and —C 2 HB 10 H 10 is closo ortho-, meta-, or para-carborane.
25. The compound according to claim 24 , wherein e, f, g, and h are 0.
26. The compound according to claim 1 wherein a, b, c, and d are 2, and Y 1 , Y 2 , Y 3 , and Y 4 are represented by
27. The compound according to claim 26 wherein D is Z, and Z is selected from the carboranes —C 2 HB 9 H 10 or —C 2 HB 10 H 10 , wherein —C 2 HB 9 H 10 is nido ortho-, meta-, or para-carborane, and —C 2 HB 10 H 10 is closo ortho-, meta-, or para-carborane.
28. The compound according to claim 27 , wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.
29. The compound according to claim 28 , wherein X 1 and X 2 are O; R 1 , R 2 , R 3 and R 4 are H; n and p are 1; and mis 2.
30. The compound according to claim 29 , wherein Y 1 , Y 2 , Y 3 , and Y 4 are in the two meta positions on each phenyl ring.
31. The compound according to claim 30 , wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 5 positions on each phenyl ring.
32. The compound according to claim 30 , wherein the —X 2 —(CR 3 R 4 ) p —D substituents are in the 3 and 4 positions on the phenyl ring.
33. The compound according to claim 31 or 32 , wherein k, l, u, and w are 0.
34. The compound according to claim 33 , wherein e, f, g, and h are 0.
35. The compound according to claim 4 , wherein X 1 and X 2 are O; R 1 , R 2 , R 3 and R 4 are H; n and p are 1; m is 2, and D is represented by
36. The compound according to claim 35 , wherein X 3 is O, R 10 and R 11 are H, s is 1, D′ is Z, q is 2, and i is 0, wherein Z is selected from the carboranes —C 2 HB 9 H 10 or —C 2 HB 10 H 10 , wherein —C 2 HB 9 H 10 is nido ortho-, meta-, or para-carborane, and —C 2 HB 10 H 10 is closo ortho-, meta-, or para-carborane.
37. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 1 ; and the imaging of said subject.
38. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 11 ; and the imaging of said subject.
39. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 18 ; and the imaging of said subject.
40. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 25 ; and the imaging of said subject.
41. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 34 ; and the imaging of said subject.
42. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 36 ; and the imaging of said subject.
43. The method according to any of claims 37 , 38 , 39 , 40 , 41 , or 42 wherein said imaging is by a method selected from magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), or positron emission tomography (PET) methods.
44. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 1 ; and the irradiation of said subject.
45. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 11 ; and the irradiation of said subject.
46. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 18 ; and the irradiation of said subject.
47. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 25 ; and the irradiation of said subject.
48. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 34 ; and the irradiation of said subject.
49. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 36 ; and the irradiation of said subject.
50. The method according to any of claims 44 , 45 , 46 , 47 , 48 , or 49 wherein said irradiation is by a method utilizing thermal or epithermal neutrons, or laser red light.
51. The method according to claim 44 , wherein said bimodal cancer treatment comprises boron neutron capture therapy (BNCT).
52. The method according to claim 44 , wherein said bimodal cancer treatment comprises photodynamic therapy (PDT).
53. The method according to claim 44 , wherein said bimodal cancer treatment utilizes single photon emission computed tomography (SPECT) or positron emission tomography (PET) wherein M is a SPECT- and/or PET-imageable radioactive metal ion.
54. The method according to claim 44 , wherein said bimodal cancer treatment utilizes magnetic resonance imaging (MRI) wherein M is a paramagnetic metal ion.
55. The compound according to claim 1 wherein the counter dianion is a porphyrin compound containing a divalent negative charge.
56. The compound according to claim 55 , wherein the porphyrin compound containing a divalent negative charge is the compound of claim 1 , with the proviso that M is absent.Cited by (0)
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